tbuckley/cabot-search huggingface dataset:
P03.07.A MRI signature in preoperative imaging predicts mesenchymal stem cell features and radioresistance in primary glioblastoma stem cell cultures
Authors: F Eckert, K Ganser, B Bender, J Schittenhelm, S Noell, N Stransky, E Hoffmann, D Zips, S Huber, F Paulsen
Journal: Neuro-Oncology (2022)

Abstract Background Recently, a molecular signature describing the mesenchymal / proneural features of primary stem-cell-enriched glioblastoma cultures was identified correlating with invasiveness, radiation sensitivity and patient-outcome. However, generating and characterizing primary cultures is time-consuming and this might hamper translation into clinical concepts. The aim of this study was to evaluate the use of standard preoperative MR imaging (T1ce and T2FLAIR sequences) to predict the molecular signature and thus enable the development of clinical treatment concepts based on the molecular properties of the individual tumors. Material and Methods For 16 patients, for whom primary stem cell enriched cultures had been characterized for their mesenchymal / proneural signature and radiation sensitivity, tumor volume (hyperintense volume in T1ce), necrosis (hypointense volume inside the tumor volume) and edema (hyperintense volume in T2FLAIR) were contoured for volumetric analysis. Volume parameters were used to calculate ratios (edema/tumor and necrosis/tumor) and a MRI signature, which was then correlated with molecular parameters and patient outcome stratified by MGMT promoter methylation. Results As expected, the prognosis of patients with MGMT-promoter-methylated tumors was better (n.s.) compared to those with unmethylated MGMT promoters. Neither molecular nor imaging data were significantly different between these subgroups. In the subgroup of patients with unmethylated MGMT promoter, volumetric imaging parameters correlated with the molecular signature and cellular radiation sensitivity of the stem cell enriched cultures. This association was much weaker in the subgroup with methylated MGMT promoter. Conclusion In the subgroup of patients with unmethylated MGMT promoter, volumetric parameters on preoperative standard MR imaging might hint at the molecular properties of the respective tumor and its radiation sensitivity. This might be a clinically applicable method to stratify treatment according to molecular stem cell subtype without tissue culture and molecular analysis.
P10.24.A A personalized BRAF mutant glioblastoma with Human2Human<i>ex-vivo</i> cortical cultures
Authors: J Zhang, K Joseph, J Beck, O Schnell, V M Ravi, D H Heiland
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma is among the most common primary malignancy with a poor medium survival post-diagnosis. The incredible heterogeneity of glioblastoma highlights its incurable nature. Methods to overcome difficulties leaded by glioblastoma heterogeneity remain to be explored. Here we present our Human2Human personalized autografted BRAF(V600E) mutant glioblastoma model, focusing on the idea of precision. This model, with an inoculation of self-derived glioblastoma cells, can imitate the tumor growth, invasion, metabolism and microenvironmental crosstalk within its “native” microenvironment and allows us to investigate the influence of different chemotherapies on the immunosuppressive tumor microenvironment from each specific individual glioblastoma patient. Material and Methods Non-neoplastic cortical tissue was obtained from a BRAF(V600E) mutant glioblastoma patient during surgical operation. Tissue was sectioned and inoculated with autografted glioblastoma cells in order to establish the ex-vivo Human2Human personalized brain slice model. Slice viability and tumor growth were monitored throughout the culture period, with and without day-wise refreshed treatments of clinically proved BRAF/MEK inhibitors. Sections were fixed and stained post cultivation. Pathway proteins p-ERK, p-Akt based on BRAF signaling along with markers (TMEM119, Iba-1, CD3, CD68, GFAP and NeuN) for major cell types in the environment were stained. Single Nuclei RNA Sequencing and Spatially Resolved Transcriptomics were applied. Results Tumor growth quantification over the culture period revealed different tumor reaction and tolerance towards various chemotherapies. The combination of Vemurafenib + Trametinib exhibited more efficient therapy response in comparison with either Dabrafenib + Trametinib or Encorafenib + Trametinib. Immunofluorescence and immunohistochemistry based quantification referring to neurons (NeuN), astrocytes (GFAP) and microglia/macrophage cells (Iba-1) suggested no toxic effects of the drug combinations on the tumor microenvironment. BRAF pathway proteins and immune cells showed various activation patterns upon different treatment combinations on an immunofluorescence base. Single Nuclei RNA Sequencing revealed the mesenchymal differentiation of BRAF mutant glioblastoma cells. Spatially Resolved Transcriptomics characterized tumor recurrence and suggested the therapy response accurately and visually. Conclusion The combination of Vemurafenib + Trametinib shows strategy to this specific BRAF mutant glioblastoma patient. And therefore, this Human2Human personalized model has a potential to provide in-depth information of the spatio-temporal tumor differentiation ex-vivo, correct inter-patient bias, and model therapy response in a very short time frame to provide drug testing results for clinical decision making.
P02.11.B An hypothesis generating study of MRI-Derived Radiomics on tumor and microenvironment tissue heterogeneity to guide post-operative management of glioblastoma: toward personalized radiation treatment volume delineation
Authors: M Cannatà, R Russo, F Beghella Bartoli, I Palumbo, H Tran, C Votta, M Lupattelli, L Boldrini, N Dinapoli, F Camilli, M Balducci, M Gambacorta, V Valentini, C Aristei, G Sabatino, F Pignotti, S Gaudino, S Chiesa
Journal: Neuro-Oncology (2022)

Abstract Background The glioblastoma’s bad prognosis is primarily due to intra-tumor heterogeneity, demonstrated from several studies that collected molecular biology, cytogenetic data and more recently radiomic features for a better prognostic stratification.The GLIFA project (GLIoblastoma Feature Analysis) is a multicentric project planned to investigated the role of radiomic analysis in GBM management, to verify if radiomic features in the tissue around the resection cavity which may guide the radiation target volume delineation. Material and Methods We retrospectively analyze from three centers radiomic features extracted from 90 patients with total or near total resection, who completed the standard adjuvant treatment and for whom we had post-operative images available for features extraction.The Manual segmentation was performed on post gadolinium T1w MRI sequence by 2 radiation oncologist reviewed by a neuroradiologist, both with at least 10 years of experience. The Region of interest (ROI) considered for the analysis were: the surgical cavity +/- post-surgical residual mass (CTV_cavity); the CTV a margin of 1.5 cm added to CTV_cavity and the volume resulting from subtracting the CTV_cavity from the CTV was defined as CTV_Ring. Radiomic analysis and modelling were conducted in RStudio. Z-score normalization was applied to each radiomic feature. A radiomic model was generated using the 226 features extracted from the Ring to perform a binary classification and predict the PFS at 6 months (statistical, morphological and textural features). A 3-fold cross-validation repeated five times was implemented for internal validation of the model. Results Two-hundred and seventy ROIs were contoured. The proposed radiomic model was given by the best fitting logistic regression model, and included the following 3 features: F_cm_merged.contrast, F_cm_merged.info.corr.2, F_rlm_merged.rlnu. A good agreement between model predicted probabilities and observed outcome probabilities was obtained (p-value of 0.49 by Hosmer and Lemeshow statistical test). The ROC curve of the model reported an AUC of 0.78 (95% CI: 0.68 - 0.88). Conclusion This is the first hypothesis-generating study who applies a radiomic analysis focusing on healthy tissue ring around the surgical cavity on post-operative MRI. This study provides a preliminary model for a decision support tool for a customization of the radiation target volume in GBM patients in order to achieve a margin reduction strategy.
P12.11.B The role of miRNAs in glioma in response to hypoxia
Authors: L C Smith, D Chakraborty, D Lourdsamy, D McIntyre, D Smith
Journal: Neuro-Oncology (2022)

Abstract Background Hypoxia, low oxygen, is a microenvironment that promotes tumour progression, particularly in gliomas. The regulation of many biological processes are maintained by miRNAs. The hypoxia status of glioma cells effects the regulation of processes by affecting the expression of individual miRNAs.The aims of this study is identifying significant miRNAs that are either under or overexpressed in hypoxia compared to normoxia in glioma cells and further exploring the effect of hypoxia on miR-92a-3p and miR-149-5p in gliomas on the apoptotic and cellular senescence pathways. Material and Methods A range of glioma cells were used for screening including primary cell lines: GIN28 and GIN31; low-grade cell lines: LGG19 and LGG24; paediatric cell line: SF188 and commercially available glioblastoma cell line U87. These cells were culture at both 1% (hypoxia) and 20% (normoxia) oxygen levels. Screening of miRNAs was achieved by quantitative polymerase chain reaction (qPCR) using miRNA specific primers. Knockdowns/in were achieved by transfecting with miR-92a-3p and miR-149-5p mimics and inhibitors. Caspase-glo assay was used to assess the effect of hypoxia on apoptosis. Results miRNA 92a-3p and miR-149-5p were found to be downregulated and upregulated respectively in primary gliomas cells in hypoxia compared to normoxia. These particular miRNAs are also found to have multiple targets in apoptosis and cellular senescence. Conclusion The screening of 90 miRNAs among the different categories of gliomas highlighted multiple miRNAs that were significant in hypoxia compared to normoxia. Using primary cell lines have identified hypoxia-affected miRNAs in glioblastomas. This discovery will increase our knowledge and understanding of the hypoxia effect on miRNAs which may aid and direct targeted therapy to conquer hypoxia in glioblastomas.
P11.15.B First multicentric real-life experience with the combination of lomustine and temozolomide in newly diagnosed<i>MGMT</i> promoter methylated<i>IDH</i> wildtype glioblastoma
Authors: L Lazaridis, T Schmidt, S Agkatsev, T Blau, D Spille, S Heider, T Schulz, E Bumes, C Oster, J Feldheim, W Stummer, A Kessler, C Seidel, P Hau, U Sure, K Keyvani, U Herrlinger, C Kleinschnitz, M Stuschke, K Herrmann, C Deuschl, E Hattingen, B Scheffler, S Kebir, M Glas
Journal: Neuro-Oncology (2022)

Abstract Background The CeTeG/NOA-09 trial assessed in a randomized phase 3 setting, whether combined treatment of lomustine together with temozolomide was superior to temozolomide treatment alone in newly diagnosed MGMT (O(6)-methylguanine-DNA-methyltransferase) promoter methylated glioblastoma patients. Survival was significantly improved from 31.4 months with temozolomide alone to 48.1 months with the combination of lomustine plus temozolomide. In view of this encouraging data - suggesting this combination could have a significant impact on the survival of newly diagnosed glioblastoma patients - we were curious to assess safety and efficacy of this regimen under real-life conditions. Material and Methods We collected clinical and radiographic data from adult newly diagnosed MGMT promoter methylated IDH (isocitrate dehydrogenase) wildtype glioblastoma patients treated at five neuro-oncology centers in Germany. As a requirement for inclusion, first-line treatment with lomustine plus temozolomide had to be performed for at least six weeks (one course). The available radiographic data was independently reviewed by an experienced board-certified neuro-radiologist. Results In total, 70 patients were included. Median progression-free survival of the full cohort was 14.4 months and median overall survival was 36.0 months. Patients who received TTFields (Tumor Treating Fields) treatment for eight weeks or longer together with the combination of lomustine plus temozolomide (n=22, 31%) had a prolonged progression-free survival compared to those patients who received TTFields treatment less than eight weeks or did not receive treatment with TTFields (n=48, 69%) (21.5 months versus 11.2 months; HR: 2.118, 95% CI: 1.245-3.605; p=0.0105). In a multivariable Cox regression analysis the use of TTFields for eight weeks or longer together with the combination of lomustine plus temozolomide as well as the application of at least five courses of CeTeG therapy emerged as independent prognostic factors for progression-free survival and overall survival. Pseudoprogression occurred in n=16 (33%) of the patients. We observed no treatment related deaths and high-grade hematotoxicity in n=31 (44%) of the patients. Conclusion The results from this multicentric trial that investigated newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma under real-life conditions indicate toxicity and survival estimates comparable to the CeTeG/NOA-09 trial. The use of TTFields for at least eight weeks in combination with this regimen was independently associated with extended progression-free and overall survival.
P10.08.A Lipogenesis inhibition by fatostatin shows effectiveness in glioblastoma models highly expressing fatty acid synthase (FASN)
Authors: L Kastler, K Neumayer, M Laaber, C Roschger, S Lenz, D Lötsch-Gojo, W Berger, A Gruber, S Spiegl-Kreinecker
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is the most common and most aggressive primary brain tumour in adults. Despite intensive treatment, the medium overall survival of GBM patients remains below 20 months after diagnosis. Therefore, new tumour specific targets allowing successful therapeutic treatment are needed to distinctly enhance GBM patient overall survival. Reprogramming of lipid metabolism leading to highly upregulated anabolic pathways, like phosphatidylinositol-3-kinase (PI3K)/AKT pathway and subsequently lipogenesis, is a hallmark of cancer cells including glioblastomas to meet increased energy demands for proliferation and cell growth. Accordingly, lipogenesis inhibition might be a promising strategy to impede GBM cell growth. Therefore, it was aim of our study to analyse the effect of the lipogenesis inhibitor fatostatin on downstream targets e.g. fatty acid synthase (FASN) and its impact on cell growth in GBM cells in vitro. Material and Methods In a cohort of 52 GBM-derived cell lines, FASN mRNA was investigated by qRT-PCR. The impact of fatostatin on cell viability (IC50) was analysed in selected cell lines using cell viability assays (Cell Titer Glo®). To elucidate whether fatostatin exposure affects cell migration, wound healing assays were performed. The effect of fatostatin on cell cycle and apoptosis was analysed by flow cytometry. Additionally, expression of FASN and level of phosphorylated AKT, the active form of AKT serine/threonine kinase, were examined before and after fatostatin treatment with qRT-PCR (mRNA) and Western blot (protein), respectively. Results FASN mRNA was found to be expressed at varying levels in our GBM-derived cell line cohort (n=52). Compared to normal astrocytes, FASN mRNA expression was significantly upregulated in GBM cells (p=0.0127). Furthermore, high FASN mRNA expression was significantly associated with higher sensitivity against fatostatin (p=0.0352). Regarding corresponding recurrences, the response to the inhibitor was shown to be persistent. Accordingly, the effectiveness of fatostatin treatment resulted in substantial downregulation of AKT phosphorylation and consequently in the induction of apoptosis and G2/M arrest of the cell cycle. In addition, a significant inhibition of the migration potential by fatostatin treatment was observed. Conclusion In summary, FASN expression represents a promising biomarker and therapy target within the lipid metabolism indicated by a significant sensitivity to fatostatin in FASN overexpressing GBM cell lines. Consequently, lipogenesis inhibition by fatostatin might be a promising novel therapeutic option in glioblastoma.
KS05.7.A Characterization of the immune composition of extreme long-term survivors with malignant glioma at single-cell level
Authors: B Decraene, A Antoranz, T Verbeke, P Nazari, L Solie, N Dubroja, M Derweduwe, F De Smet, S De Vleeschouwer
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma Multiforme (GBM) remains the most common malignant primary brain tumor with a dismal prognosis that rarely exceeds beyond two years despite extensive therapy, which consists of maximal safe surgical resection, radiotherapy and/or chemotherapy. Recently, it has become clear that GBM is not one homogeneous entity and that both intra-and intertumoral heterogeneity contribute significantly to differences in tumoral behavior which may consequently be responsible for differences in survival. Strikingly and in spite of its dismal prognosis, small fractions of GBM patients seem to display extended survival compared to the large majority of patients. The underlying mechanisms for this peculiarity remain largely unknown however, even though emerging data suggest that both cancer cell-autonomous and microenvironmental factors and their interplay probably play an important role. Material and Methods We used high-dimensional, multiplexed immunohistochemistry to spatially, and cytometry by time-of-flight to quantitively characterize the cell constitution and interactions within the tumor microenvironment (TME) in 21 extreme long-term survivors (living over ten years since primary diagnosis or five years after recurrence) and 42 deeply matched short-term controls (living under 1.5 year) on a single cell level. For all tumors (epi-)genetic data was also collected. Results We identified a high level of both inter-and intrapatient heterogeneity defined by several distinct tumor niches, as well as described interactions within these niches and with the surrounding infiltrating immune cells of the TME. By linking patient characteristics with the heterogeneous immune composition we are building an immune stratification that can be linked to patient survival in GBM. Conclusion Generating an immune stratification for GBM will allow us to identify immune characteristics responsible for longer or even exceptional survival, as well as thoroughly identify tumor components that may serve as a potential target for personalized treatment strategies. Therefore, this study is also an essential initial step towards such clinical trials which alter the TME in a favorable way with a personalized modulation strategy.
P11.52.A Peripheral neuropathies after BRAF and/or MEK inhibitors treatment: a pharmacovigilance study
Authors: A Picca, C Birzu, G Berzero, P Sanchez-Pena, L Gaboriau, F Vidil, T Lenglet, C Tafani, D Ricard, D Psimaras, K Bihan
Journal: Neuro-Oncology (2022)

Abstract Background BRAF (BRAFi) and MEK inhibitors (MEKi) demonstrated significant efficacy in the treatment of BRAF-activated tumours, firstly melanoma. Nevertheless, they are not devoid of adverse events. Sparse reports in the literature suggest the potential occurrence of peripheral neuropathies (PN) under BRAFi/MEKi treatment, but their characteristics remain poorly defined. We aimed to characterize the clinical phenotypes of PN occurring under BRAFi/MEKi treatment using a national pharmacovigilance database. Material and Methods We queried the French pharmacovigilance database for all cases of PN toxicity attributed to at least one BRAFi or MEKi compound. Only cases with a least symptoms description and nerve conduction studies (NCS) conclusion were included. Results Sixteen cases of PN occurred in 15 patients were identified. All patients had underlying melanoma. Two main phenotypes were seen. Six patients (dabrafenib-trametinib, n=3; vemurafenib, n=2; vemurafenib-cobimetinib, n=1) presented a length-dependent axonal polyneuropathy: symptoms were mostly sensory at lower limbs; NCS disclosed an axonal neuropathy; management and outcome were variable. Nine patients (dabrafenib-trametinib, n=5, encorafenib-binimetinib, n=3, and vemurafenib-cobimetinib, n=1) developed a demyelinating polyradiculoneuropathy: symptoms affected the four limbs and included hypoesthesia, weakness, and ataxia; cranial nerves were involved in four; NCS showed predominantly demyelinating features; most patients received intravenous immunoglobulins (n=6) or glucocorticoids (n=5), but the outcome was variable; one patient was rechallenged with a different BRAFi/MEKi with a rapid relapse. Conclusion Patients under treatment with BRAFi/MEKi may develop treatment-induced PN. Two main phenotypes are seen: a symmetric, axonal, length-dependent polyneuropathy, and a demyelinating polyradiculoneuropathy.
P11.38.A Case reports on aggressive Pilocytic astrocytoma in TYA and adults: patient tailored approach or standard of care?
Authors: S Gupta, L Brazil, A Swampillai, O Al-Salihi
Journal: Neuro-Oncology (2022)

Abstract Background Pilocytic astrocytoma (piloA) is a low grade brain tumour and most of the literature is based on paediatric patients with limited data on adults. Surgical resection followed by adjuvant treatment for recurrent lesions is standard of care. While previous literature was mainly based on historical classification, molecular analysis of tumour is adding to the subgroup classification. Material and Methods We are reporting 3 cases of adult piloA treated at our institute. Results: Case1 31y female with headaches and visual problems was diagnosed with optic nerve glioma, biopsy confirmed piloA, and was treated with conventional radiotherapy 50Gy/30fr. A month later developed CSF dissemination requiring 10xTemozolamide. Two years later, developed L5 and S2 deposits which were resected and confirmed piloA. 5 years later there was progression of primary disease treated with 12xTemozolamide and a year later developed further progression and hydrocephalus. She received 1xPCV and succumbed to disease at the age of 42. Case 2: 29y female with severe dizziness on moving head, worsening headaches, word finding difficulty, and positive family history of anaplastic astrocytoma, was diagnosed with Tectal plate lesion. Surgical debulking was performed and pathology showed piloA with Methylated MGMT promoter, IDH wild-type, H3K27M negative, and no BRAF fusion. 3 years later developed recurrence which was treated with chemotherapy (5xPCV: 6th omitted due to recurrent infections) as patient was reluctant for radiotherapy. Follow up scans 6 months post chemotherapy remain stable. Case 3: 24y female with background of 2 haemorrhagic strokes, left spastic hemi-paralysis and left hemianopia, and negative family history, had a biopsy performed for Right Mesotemopral Cavenous Angioma. Pathology showed low grade neoplasm favouring Ganglioglioma with CD34 and IDH1 negative, ATRX retained, KI-67 focal index 5%, and no BRAF fusion or mutation. Surveillance imaging showed progressively increasing suprasellar mass and right temporal region enhancement which was surgically debulked at the age of 27. Repeat pathology examination favoured piloA considering the radiological progression. Methylation array failed but immunohistochemistry showed tumour cells positive with synaptophysin, ATRX and trimethylated H3K27 retained, H3K27M, NeuN, H3G34R and CD34 negative, p53 negative, and Ki-67 3-4%. Repeat imaging 10 months later showed further progressive suprasellar tumour and enhancing lesion in the right temporal area accompanied by rapid loss of right side vision. We have planned for radical radiotherapy 54Gy/30fr with IMRT. Conclusion There is a gap in management of piloA in adults with treatment extrapolated from paediatrics and does require further research. We want to approach other centres to establish consensus on treating such cases.